PROJECTSUMMARY HIVinfection,aswellasexposuretoopioidsincludingintravenousheroin,areassociatedwithsystemicimmune activation including increased microbial translocation from the gut. The overall objective of this study is to provideclinicalevidenceonthedetrimentallinkbetweenkineticsandcharacteristicsofimmunereconstitution (microbial translocation, residual immune activation, retained HIV expression) in HIV-1 infected people who inject drugs (PWIDs) and sustain interaction with the ?-opioid receptor (MOR) while on antiretroviral therapy (ART). Defining the impact of continued MOR engagement after ART initiation is of relevance to addiction treatment as maintenance-assisted treatment options include using a MOR agonist (methadone, MET) or a MOR antagonist (long-acting naltrexone, XR-NTX). Notably, the effect of oral MET, which is widely used in maintenance treatment, on ART-mediated immune reconstitution is unknown. Based on preliminary data showing higher microbial translocation, immune activation, and active HIV transcription in ART-suppressed PWIDonMEToverXR-NTR,wewilltesttheprimaryhypothesisthatchronicengagementofmu-opioidreceptor byafullMORagonist(MET)whileonARTwillresultinreducedratesandmagnitudeofmicrobialtranslocation, with sustained immune activation and inflammation associated with increased levels of persistent HIV (i.e., integratedHIVDNA,cell-associatedHIVRNA)whencomparedtoafullMORantagonist(XR-NTX)inspiteof viral suppression. Specifically, we will test these hypotheses in the following specific aims: Specific Aim 1. Defining the impact of long-term MOR stimulation (MET) or blockage (XR-NTX) on the kinetics and extent of immunereconstitutioninPWIDinitiatingART. Tothisend,wewillalsocompare48weekchangesonresidual immune activation, microbial translocation, and systemic inflammation in a cohort of PWID with chronic HIV infectioninitiatingART,randomized1:1toeitherMETorXR-NTX.sCD14levelchangeafterARTwillserveas the primary end-point variable. Specific Aim 2. Defining the clinical and virologic correlates of 48 week treatmentwithMORagonists(MET)andantagonists(XR-NTX),bystudyingeffectoftheinterventiononCD4, adherencetoART,acceptabilityofMAT,aswellasretentionincare.ChangesinpersistentHIVmeasureswill also be measured (i.e., persistence of viral RNA and DNA species in PBMC,etc.). Given the high prevalence ofHIV-infectedheroinusersstartingARTandopioidadditiontherapy,Vietnamisanidealsettingtocomplete the proposed study to provide generalizable proof-of-concept data in support of future long-term clinical outcome studies. This study represents an international multi-disciplinary collaboration between the Vietnam Ministry of Health, the Vietnam Administration of HIV/AIDS Control, the Provincial AIDS Committee, the University of Pennsylvania, Expertise France (a French-led initiative to expand access to HIV/ Hepatitis preventionandtreatmentservices),thePasteurInstitute,Alkermes(industrypartner),andTheWistarInstitute.